%0 Journal Article %A A E Mutlib %A J Jurcak %A N Hrib %T Metabolism of an atypical antipsychotic agent, 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2, 5,5-trimethyl-4-thiazolidinone (HP236). %D 1996 %J Drug Metabolism and Disposition %P 1139-1150 %V 24 %N 10 %X Metabolism of an atypical antipsychotic agent, 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2, 5,5-trimethyl-4-thiazolidinone (HP236) by rats is described. HP236 was extensively metabolized both in vitro and in vivo. Metabolites were identified using electrospray interface-LC/MS (ESI-LC/MS) and 1H NMR spectroscopy. Protonated molecular ions, MH+, were observed for all the metabolites of HP236 using ESI-LC/MS. Tandem MS was performed on these quasimolecular ions to provide structural information. Structures of metabolites were confirmed by chromatographic and spectroscopic comparisons to synthetic standards. Metabolic pathways for HP236 both in vivo and in vitro included: a) cleavage of the thiazolidinone ring structure to give N-acetyl-N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]butyl]-2-methyl-propanamide, N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]-butyl]-2-methyl-propanamide, and N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]butyl]-acetamide; b) oxidation of the sulfide to give a mixture of sulfoxide diastereoisomers, 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-1-oxo-2, 5,5-trimethyl-4-thiazolidinone and a sulfone, 1,1-dioxo-3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl ]-2, 5,5-trimethyl-4-thiazolidinone; and c) N-dealkylation at the piperazine ring to produce 3-(4-(1-piperazinyl]butyl]-2, 5,5-trimethyl-4-thiazolidinone and 6-fluoro-3-(1-piperazinyl)benzo[b]thiophene. Metabolites found circulating in the plasma of rats dosed with HP236 were identical to those produced in vitro using rat liver microsomes or S9 fractions; however, LC/MS analysis of rat urine extract showed that the metabolite profile was different than that obtained from plasma or from in vitro extracts. The metabolite resulting from the cleavage of the thiazolidinone ring, N-acetyl-N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]-butyl]-2-methyl-propanamide, was the major circulating metabolite in the plasma of rats dosed with HP236. Results from in vitro studies showed that the metabolite was also produced by incubating the sulfoxides and sulfone analogs of HP236 with rat liver microsomes. A mechanism for the formation of N-acetyl-N-[4-[4-(6-fluorobenzo [b]thien-3-yl)-1-piperazinyl]butyl]-2-methyl-propanamide from HP236 is proposed. %U https://dmd.aspetjournals.org/content/dmd/24/10/1139.full.pdf